U12, a UDCA Derivative, Acts as an Anti-Hepatoma Drug Lead and Inhibits the mTOR/S6K1 and Cyclin/CDK Complex Pathways

被引：10

作者：

Xu, Yang ^{[1
]}

Luo, Qiang ^{[1
]}

Lin, Ting ^{[1
]}

Zeng, Zhiping ^{[1
]}

Wang, Guanghui ^{[1
]}

Zeng, Dequan ^{[1
]}

Ding, Rong ^{[1
]}

Sun, Cuiling ^{[1
]}

Zhang, Xiao-kun ^{[1
,2
]}

Chen, Haifeng ^{[1
]}

机构：

[1] Xiamen Univ, Sch Pharmaceut Sci, Xiamen, Fujian, Peoples R China

[2] Sanford Burnham Med Res Inst, La Jolla, CA USA

来源：

PLOS ONE | 2014年 / 9卷 / 12期

基金：

中国国家自然科学基金;

关键词：

URSODEOXYCHOLIC ACID UDCA; COLON-CANCER CELLS; HEPATOCELLULAR-CARCINOMA; MTOR INHIBITOR; MITOCHONDRIAL DYSFUNCTION; INDUCE APOPTOSIS; BINDING-PROTEIN; LIVER; GROWTH; EXPRESSION;

D O I：

10.1371/journal.pone.0113479

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

U12, one of 20 derivatives synthesized from ursodeoxycholic acid (UDCA), has been found to have anticancer effects in liver cancer cell lines (SMMC-7721 and HepG2) and to protect normal liver cells from deoxycholic acid (DCA) damage (QSG-7701). Its anticancer mechanism was investigated using computer-aided network pharmacology and comparative proteomics. Results showed that its anti-malignancy activities were activated by mTOR/S6K1, cyclinD1/CDK2/4 and caspase-dependent apoptotic signaling pathways in hepatocellular carcinoma cells (HCC). The action of U12 may be similar to that of rapamycin. Animal testing confirmed that U12 exerted better anti-tumor activity than UDCA and had less severe side effects than fluorouracil (5-Fu). These observations indicate that U12 differs from UDCA and other derivatives and may be a suitable lead for the development of compounds useful in the treatment of HCC.

引用

页数：19

共 39 条

[1] Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence [J].

Alberts, DS ;

Martínez, ME ;

Hess, LM ;

Einspahr, JG ;

Green, SB ;

Bhattacharyya, AK ;

Guillen, J ;

Krutzsch, M ;

Batta, AK ;

Salen, G ;

Fales, L ;

Koonce, K ;

Parish, D ;

Clouser, M ;

Roe, D ;

Lance, P .

JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2005, 97 (11) :846-853

[2] Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107) [J].

Amadori, Sergio ;

Stasi, Roberto ;

Martelli, Alberto M. ;

Venditti, Adriano ;

Meloni, Giovanna ;

Pane, Fabrizio ;

Martinelli, Giovanni ;

Lunghi, Monia ;

Pagano, Livio ;

Cilloni, Daniela ;

Rossetti, Elena ;

Di Raimondo, Francesco ;

Fozza, Claudio ;

Annino, Luciana ;

Chiarini, Francesca ;

Ricci, Francesca ;

Ammatuna, Emanuele ;

La Sala, Edoardo ;

Fazi, Paola ;

Vignetti, Marco .

BRITISH JOURNAL OF HAEMATOLOGY, 2012, 156 (02) :205-212

[3] p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis [J].

Amaral, Joana D. ;

Castro, Rui E. ;

Sola, Susana ;

Steer, Clifford J. ;

Rodrigues, Cecilia M. P. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (47) :34250-34259

[4] p53 and the regulation of hepatocyte apoptosis: implications for disease pathogenesis [J].

Amaral, Joana D. ;

Castro, Rui E. ;

Steer, Clifford J. ;

Rodrigues, Cecilia M. P. .

TRENDS IN MOLECULAR MEDICINE, 2009, 15 (11) :531-541

[5] Cellular and molecular mechanisms of hepatocellular carcinoma: an update [J].

Aravalli, Rajagopal N. ;

Cressman, Erik N. K. ;

Steer, Clifford J. .

ARCHIVES OF TOXICOLOGY, 2013, 87 (02) :227-247

[6]

Aravalli RN, 2012, ARCH TOXICOL

[7]

Asciutti S, 2009, ANTICANCER RES, V29, P4971

[8] In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function [J].

Barilli, Amelia ;

Visigalli, Rossana ;

Sala, Roberto ;

Gazzola, Gian C. ;

Parolari, Alessandro ;

Tremoli, Elena ;

Bonomini, Sabrina ;

Simon, Alexandra ;

Closs, Ellen I. ;

Dall'Asta, Valeria ;

Bussolati, Ovidio .

CARDIOVASCULAR RESEARCH, 2008, 78 (03) :563-571

[9] Experimental Therapy of Ovarian Cancer with Synthetic Makaluvamine Analog: In Vitro and In Vivo Anticancer Activity and Molecular Mechanisms of Action [J].

Chen, Tao ;

Xu, Yi ;

Guo, He ;

Liu, Yanling ;

Hu, Pingting ;

Yang, Xinying ;

Li, Xiaoguang ;

Ge, Shichao ;

Velu, Sadanandan E. ;

Nadkarni, Dwayaja H. ;

Wang, Wei ;

Zhang, Ruiwen ;

Wang, Hui .

PLOS ONE, 2011, 6 (06)

[10] Apoptosis and modulation of cell cycle control by synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid in human prostate cancer cells [J].

Choi, YH ;

Im, EO ;

Suh, H ;

Jin, YG ;

Yoo, YH ;

Kim, ND .

CANCER LETTERS, 2003, 199 (02) :157-167

← 1 2 3 4 →